The invention relates to a floatable, oral therapeutic system. Oral therapeutic systems are active substance-containing means, which deliver the active substances in controlled manner to their environment.
Apart from the problem of controlled active substance delivery, such as is known in connection with the known transdermal, transmucosal, sublingual, nasal, vaginal and transplantable systems, in the case of oral therapeutic systems additional problems occur in connection with keeping the system sufficiently long in the stomach or gastrointestinal tract, the place where the active substance is to be delivered. This so-called gastrointestinal residence time is subject to very significant individual differences and is inter alia dependent on the nutritional habits of the individual.
Attempts have been made to exert an influence on the gastrointestinal residence time of medicaments by increasing the same. Thus, it has e.g. been proposed to use medicament forms, which stick to the stomach and/or intestinal wall (Drug Development and Industrial-Pharmacy, 9(7) 1316-19, (1983). Attempts have also been made to use materials which swell strongly in the stomach and can consequently not pass through the pylorus, so that their large volume brings the stomach into a fed-up state. They suppress the periodically occurring, violent peristaltic movements occurring in the case of an empty stomach and as a result of which larger food particles can pass into the intestine. It has finally been proposed to use for this purpose systems, which are specifically lighter than the gastric fluid, which float on the latter and can only pass with difficulty to the lower lying pylorus.
Thus, e.g. U.S. Pat. No. 4,167,558 describes a floatable tablet, which floats in the gastrointestinal fluid solely as a result of the low specific gravity of its matrix formulation. U.S. Pat. No. 4,055,178 proposes a flat system provided with a floating chamber. U.S. Pat. Nos. 3,901,232 and 3,786,831 describe systems, in which a specifically lower weight leads to inflation in the stomach through the evaporation of a physiologically unobjectionable fluid boiling at a temperature which is below body temperature.
The hithereto known solutions of this problem suffered from serious disadvantages. In the case of U.S. Pat. No. 4,167,558, matrix materials with an adequately low specific gravity must be used, so that only a limited selection is possible. In the case of the flat system of U.S. Pat. No. 4,055,178 provided with a floating chamber, certain geometrical characteristics are predetermined and cannot be obviated. The systems described in U.S. Pat. Nos. 3,901,232 and 3,786,831 have a complicated structure and require high manufacturing expenditure.
The problem of the present invention is therefore to develop novel, floatable, oral therapeutic systems, which do not suffer from the above disadvantages.
This problem is solved by a therapeutic system comprising at least one structural element with cavities, such as foams or hollow bodies.
Further advantageous developments can be gathered from the following description.
It may be advantageous that the structural elements are homogeneously distributed in the system. The structural element can be film-like. The structural element may surround the active substance.
The structural element or elements may have a polymer, such as polyethylene, polypropylene, polyamide, polystyrene, polyester, polyacrylate, polytetrafluoroethylene, polyvinyl chloride, polyvinylidene chloride, copolymers from the monomers on which said polymers are based, or polysiloxane.
It may comprise also an inorganic material, e.g. glass or ceramic material.
In a preferred embodiment of the invention the system comprises a control membrane for active substance delivery.
It may have an active substance-containing hot melt material in which the structural elements are embedded.
The structural element or elements are embedded in an active substance-containing shaped article.
The shaped article can be a hydrogel or it can form a hydrogel on contact with the gastrointestinal fluid.
The system may comprise floatable subsystems, the central parts of which are structural elements with a high cavity proportion, said structural elements being provided with an active substance-containing coating or having active substances.
The subsystems may be enclosed in a capsule soluble under physiological conditions.
The floatable subsystems can be combined by a binder to form a shaped article, whereby optionally the subsystems can be released on contact with the gastric and/or intestinal fluid, which dissolves the binder.
The system may have various layers and at least one layer is a floatable structural element.
The system may be folded or rolled together prior to administration and may unfold or unroll under stomach conditions.
Advantageously the system is completely or partly decomposable under physiological conditions.
It has surprisingly been found that through the use of materials having a high void proportion or gas cavities, it is possible to manufacture oral systems with a low specific gravity. Suitable materials are e.g. foams or hollow spheres, which can be made from the most varied materials, e.g. from all thermoplastic polymers, natural polymers and inorganic compounds, such as glasses and ceramic materials.
In particular foam-like or microporous structures of thermoplastic polymers in the form of powders, film, rods and hoses are commercially available.
The penetration of water into pores can be prevented by an adequately small pore size (by capillary effects) or by the use of hydrophobic polymers, which prevent the access of water, particularly into voids in the interior of polymers, provided that the pore size is sufficiently small.
It is possible to use glass spheres of small diameter, such as are commercially available, as hollow bodies for reducing the specific gravity of the system.
DE-OS 32 15 211 describes a process for the production of microporous powders filled or charged with active substance. In this case, at elevated temperature, a homogeneous polymer solution is atomized into a gas, whereby demixing occurs between the polymer and solvent. After removing the solvent, particles with a microporous structure are left behind. If active substance is added during the production of the microporous particles, or the pore forming agent is itself the active substance, active substance-containing microporous powders are obtained.
EP-A2-0 146 740 discloses a process for the production of shaped articles with a microporous structure from microporous powders using a pressing or compressing process. Possibilities are given for filling or charging the microporous shaped articles with active substances prior to compression.
EP-A2-0 162 492 describes a tablet with a membrane controlling active substance delivery and which is produced from microporous powders by a pressing or compressing process.
The present invention is characterized in that use is made of microporous substances or structures, which have a low specific gravity and which are maintained for a sufficiently long time under the conditions in the stomach. In no case are all the voids of the structural elements filled with active substances. Adequate cavities are always left free to ensure a low specific gravity in order to maintain the floatability of the system.
A particular advantage of the invention is that systems can be filled with active substance by up to 70% by volume and up to 80% by weight. It is also possible to additionally coat the systems filled with active substance with a control coating, e.g. a membrane controlling via the pore size, or a membrane controlling via the diffusion rate, in order to be able to perform further control functions.